Joseph A Buonomo | Stanford University (original) (raw)

Papers by Joseph A Buonomo

ChemBioChem, 2020

In this viewpoint, the concepts that chemistry transcends the laboratory into the clinic and beyo... more In this viewpoint, the concepts that chemistry transcends the laboratory into the clinic and beyond is explored from the perspective of a single individual who began strictly within synthetic chemistry. They learned through their training that in reality, chemists are capable of anything, requiring mentorship, open discussion, and some frontend work to learn something new.

Synthesis, 2017

A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The prepar... more A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The preparation of similar symmetrical disiloxane materials is also accomplished with this same protocol. This mechano-chemical procedure is efficient and highly scalable, furnishing a convenient route to hydrido-disiloxanes from widely accessible commercially available silanes.

Chemistry – A European Journal, 2017

Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward... more Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward method to prepare these valuable reagents. However, existing methods to reduce phosphine oxides suffer from inadequate chemoselectivity due to the strength of the P=O bond and/or poor atom economy. Herein, we report the discovery of the most powerful chemoselective reductant for this transformation to date, 1,3-diphenyl-disiloxane (DPDS). Additive-free DPDS selectively reduces both secondary and tertiary phosphine oxides with retention of configuration even in the presence of aldehyde, nitro, ester, α,β-unsaturated carbonyls, azocarboxylates, and cyano functional groups. Arrhenius analysis indicates that the activation barrier for reduction by DPDS is significantly lower than any previously calculated silane reduction system. Inclusion of a catalytic Brønsted acid further reduced the activation barrier and led to the first silane-mediated reduction of acyclic phosphine oxides at room temperature.

Scientific Reports, 2016

The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel trea... more The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. Tuberculosis (TB) causes over 1.7 million deaths per year and an estimated two billion people latently infected with Mycobacterium tuberculosis provides a large reservoir for ongoing reactivation and transmission of disease 1,2. Treatment options for TB are longer and more complex than treatments for other bacterial infections. These complex therapies have led to patient non-compliance and disrupted treatment, resulting in an increased incidence of multidrug resistant and extensively drug resistant M. tuberculosis infections 1,3. The search for new therapeutic options for treatment of drug susceptible as well as drug resistant strains has fueled an effort to repurpose existing drugs for TB therapy 4,5. Sulfonamides are broad spectrum antimicrobials commonly used to treat many bacterial infections 6,7. These compounds are structurally similar to p-aminobenzoic acid (PABA), an essential precursor for synthesis of tetrahydrofolate. This structural similarity enables competitive inhibition of dihydropteroate synthase (DHPS) by sulfonamides thereby leading to disruption of tetrahydrofolate biosynthesis (Fig. 1a) 9. In addition, it has been shown that sulfonamides can serve as alternative substrates for DHPS leading to the depletion of dihydropterin pools with the synthesis of dead end products that might further impair tetrahydrofolate biosynthesis 9,10. Sulfonamides were used in early experimental TB therapy, but were replaced by the more potent anti-tubercular agents streptomycin and p-aminosalicylic acid (PAS) 11-13. Dapsone, another PABA analog and DHPS inhibitor, is a cornerstone in treatment of infections with the related species Mycobacterium leprae. Yet, due to moderate potency and the extent of adverse drug reactions, this drug is not used for M. tuberculosis infections. Despite the limited utility of sulfonamides and dapsone against M. tuberculosis infection, enzymatic studies have confirmed that these compounds are potent competitive inhibitors for purified recombinant

Chemistry – A European Journal

Synthesis

The recently reported chemoselective reduction of phosphine oxides with 1,3-diphenyldisiloxane (D... more The recently reported chemoselective reduction of phosphine oxides with 1,3-diphenyldisiloxane (DPDS) has opened up the possibility of additive-free phosphine oxide reductions in catalytic systems. Herein we disclose the use of this new reducing agent as an enabler of phosphorus redox recycling in Wittig, Staudinger, and alcohol substitution reactions. DPDS was successfully utilized in ambient-temperature additive-free redox recycling variants of the Wittig olefination, Appel halogenation, and Staudinger reduction. Triphenylphosphine-promoted catalytic recycling reactions were also facilitated by DPDS. Additive-free triphenylphosphine-promoted catalytic Staudinger reductions could even be performed at ambient temperature due to the rapid nature of phosphinimine reduction, for which we characterized kinetic and thermodynamic parameters. These results demonstrate the utility of DPDS as an excellent reducing agent for the development of phosphorus redox recycling reactions.

Several lipids of the pathogen Mycobacterium tuberculosis are known to promote virulence at vario... more Several lipids of the pathogen Mycobacterium tuberculosis are known to promote virulence at various stages of disease. However, the inability to probe these lipids during in vivo infection makes elucidation of their pathogenic mechanisms difficult. Using chemical extraction and reconstitution methods, we were able to define the lipid composition of the outer mycomembrane of Mycobacterium marinum prior to infection. Combining this approach with the synthesis of clickable, semi-synthetic lipids, we introduced a chemically tractable, biologically active variant of the virulence lipid phthiocerol dimycocerosate (PDIM) into the mycomembrane. We find that following infection of zebrafish larvae, PDIM spreads away from bacterial surfaces into the membranes of both macrophage and epithelial cells that it contacts. This spreading facilitates PDIM′s role in preventing bacterium-detrimental immune activation at the site of infection.

Angewandte Chemie, 2015

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance... more The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance,b ut has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichiometric phosphine oxide and hydrazine by-products that complicate purification. Ac atalytic Mitsunobu reaction using innocuous reagents to recycle these by-products would overcome both of these shortcomings.Herein we report aprotocol that is catalytic in phosphine (1-phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchis azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction. Scheme 1. Proposed catalytic Mitsunobu reaction.

Synthesis, 2018

A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The prepar... more A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The preparation of similar symmetrical disiloxane materials is also accomplished with this same protocol. This mechano-chemical procedure is efficient and highly scalable, furnishing a convenient route to hydrido-disiloxanes from widely accessible commercially available silanes.

Chemistry, a European Journal, 2017

Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward... more Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward method to prepare these valuable reagents. However, existing methods to reduce phosphine oxides suffer from inadequate chemoselectivity due to the strength of the P=O bond and/or poor atom economy. Herein, we report the discovery of the most powerful chemoselective reductant for this transformation to date, 1,3-diphenyl-disiloxane (DPDS). Additive-free DPDS selectively reduces both secondary and tertiary phosphine oxides with retention of configuration even in the presence of aldehyde, nitro, ester, a,b-unsaturated carbonyls, azocarboxylates, and cyano functional groups. Arrhenius analysis indicates that the activation barrier for reduction by DPDS is significantly lower than any previously calculated silane reduction system. Inclusion of a catalytic Brønsted acid further reduced the activation barrier and led to the first silane-mediated reduction of acyclic hosphine oxides at room temperature.

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates, 2016

The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel trea... more The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. Tuberculosis (TB) causes over 1.7 million deaths per year and an estimated two billion people latently infected with Mycobacterium tuberculosis provides a large reservoir for ongoing reactivation and transmission of disease 1,2. Treatment options for TB are longer and more complex than treatments for other bacterial infections. These complex therapies have led to patient non-compliance and disrupted treatment, resulting in an increased incidence of multidrug resistant and extensively drug resistant M. tuberculosis infections 1,3. The search for new therapeutic options for treatment of drug susceptible as well as drug resistant strains has fueled an effort to repurpose existing drugs for TB therapy 4,5. Sulfonamides are broad spectrum antimicrobials commonly used to treat many bacterial infections 6,7. These compounds are structurally similar to p-aminobenzoic acid (PABA), an essential precursor for synthesis of tetrahydrofolate. This structural similarity enables competitive inhibition of dihydropteroate synthase (DHPS) by sulfonamides thereby leading to disruption of tetrahydrofolate biosynthesis (Fig. 1a) 9. In addition, it has been shown that sulfonamides can serve as alternative substrates for DHPS leading to the depletion of dihydropterin pools with the synthesis of dead end products that might further impair tetrahydrofolate bio-synthesis 9,10. Sulfonamides were used in early experimental TB therapy, but were replaced by the more potent anti-tubercular agents streptomycin and p-aminosalicylic acid (PAS) 11-13. Dapsone, another PABA analog and DHPS inhibitor, is a cornerstone in treatment of infections with the related species Mycobacterium leprae. Yet, due to moderate potency and the extent of adverse drug reactions, this drug is not used for M. tuberculosis infections. Despite the limited utility of sulfonamides and dapsone against M. tuberculosis infection, enzy-matic studies have confirmed that these compounds are potent competitive inhibitors for purified recombinant

Angewandte Chemie International Edition, 2015

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance... more The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance,b ut has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichio-metric phosphine oxide and hydrazine by-products that complicate purification. Ac atalytic Mitsunobu reaction using innocuous reagents to recycle these by-products would overcome both of these shortcomings.Herein we report aprotocol that is catalytic in phosphine (1-phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchis azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.

Synthesis, 2013

A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyri... more A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyridine is presented. 5,5′-Bis(trifluoromethyl)-2,2′-bipyridine
is also synthesized by the same protocol. The syntheses efficiently couple the parent 2-chloropyridines by a nickel-catalyzed dimerization with manganese powder as the terminal reductant.

Synlett, 2014

The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two different el... more The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two different electrophiles, 2-chloropyridines with alkyl bromides, is described. Compared to our previously published conditions for aryl halides, this method uses the different, more rigid bathophenanthroline ligand and is conducted at high concentration in DMF solvent. The method displays promising functional group compatibility and the conditions are orthogonal to the Stille coupling.

ChemBioChem, 2020

In this viewpoint, the concepts that chemistry transcends the laboratory into the clinic and beyo... more In this viewpoint, the concepts that chemistry transcends the laboratory into the clinic and beyond is explored from the perspective of a single individual who began strictly within synthetic chemistry. They learned through their training that in reality, chemists are capable of anything, requiring mentorship, open discussion, and some frontend work to learn something new.

Synthesis, 2017

A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The prepar... more A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The preparation of similar symmetrical disiloxane materials is also accomplished with this same protocol. This mechano-chemical procedure is efficient and highly scalable, furnishing a convenient route to hydrido-disiloxanes from widely accessible commercially available silanes.

Chemistry – A European Journal, 2017

Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward... more Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward method to prepare these valuable reagents. However, existing methods to reduce phosphine oxides suffer from inadequate chemoselectivity due to the strength of the P=O bond and/or poor atom economy. Herein, we report the discovery of the most powerful chemoselective reductant for this transformation to date, 1,3-diphenyl-disiloxane (DPDS). Additive-free DPDS selectively reduces both secondary and tertiary phosphine oxides with retention of configuration even in the presence of aldehyde, nitro, ester, α,β-unsaturated carbonyls, azocarboxylates, and cyano functional groups. Arrhenius analysis indicates that the activation barrier for reduction by DPDS is significantly lower than any previously calculated silane reduction system. Inclusion of a catalytic Brønsted acid further reduced the activation barrier and led to the first silane-mediated reduction of acyclic phosphine oxides at room temperature.

Scientific Reports, 2016

The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel trea... more The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. Tuberculosis (TB) causes over 1.7 million deaths per year and an estimated two billion people latently infected with Mycobacterium tuberculosis provides a large reservoir for ongoing reactivation and transmission of disease 1,2. Treatment options for TB are longer and more complex than treatments for other bacterial infections. These complex therapies have led to patient non-compliance and disrupted treatment, resulting in an increased incidence of multidrug resistant and extensively drug resistant M. tuberculosis infections 1,3. The search for new therapeutic options for treatment of drug susceptible as well as drug resistant strains has fueled an effort to repurpose existing drugs for TB therapy 4,5. Sulfonamides are broad spectrum antimicrobials commonly used to treat many bacterial infections 6,7. These compounds are structurally similar to p-aminobenzoic acid (PABA), an essential precursor for synthesis of tetrahydrofolate. This structural similarity enables competitive inhibition of dihydropteroate synthase (DHPS) by sulfonamides thereby leading to disruption of tetrahydrofolate biosynthesis (Fig. 1a) 9. In addition, it has been shown that sulfonamides can serve as alternative substrates for DHPS leading to the depletion of dihydropterin pools with the synthesis of dead end products that might further impair tetrahydrofolate biosynthesis 9,10. Sulfonamides were used in early experimental TB therapy, but were replaced by the more potent anti-tubercular agents streptomycin and p-aminosalicylic acid (PAS) 11-13. Dapsone, another PABA analog and DHPS inhibitor, is a cornerstone in treatment of infections with the related species Mycobacterium leprae. Yet, due to moderate potency and the extent of adverse drug reactions, this drug is not used for M. tuberculosis infections. Despite the limited utility of sulfonamides and dapsone against M. tuberculosis infection, enzymatic studies have confirmed that these compounds are potent competitive inhibitors for purified recombinant

Chemistry – A European Journal

Synthesis

The recently reported chemoselective reduction of phosphine oxides with 1,3-diphenyldisiloxane (D... more The recently reported chemoselective reduction of phosphine oxides with 1,3-diphenyldisiloxane (DPDS) has opened up the possibility of additive-free phosphine oxide reductions in catalytic systems. Herein we disclose the use of this new reducing agent as an enabler of phosphorus redox recycling in Wittig, Staudinger, and alcohol substitution reactions. DPDS was successfully utilized in ambient-temperature additive-free redox recycling variants of the Wittig olefination, Appel halogenation, and Staudinger reduction. Triphenylphosphine-promoted catalytic recycling reactions were also facilitated by DPDS. Additive-free triphenylphosphine-promoted catalytic Staudinger reductions could even be performed at ambient temperature due to the rapid nature of phosphinimine reduction, for which we characterized kinetic and thermodynamic parameters. These results demonstrate the utility of DPDS as an excellent reducing agent for the development of phosphorus redox recycling reactions.

Several lipids of the pathogen Mycobacterium tuberculosis are known to promote virulence at vario... more Several lipids of the pathogen Mycobacterium tuberculosis are known to promote virulence at various stages of disease. However, the inability to probe these lipids during in vivo infection makes elucidation of their pathogenic mechanisms difficult. Using chemical extraction and reconstitution methods, we were able to define the lipid composition of the outer mycomembrane of Mycobacterium marinum prior to infection. Combining this approach with the synthesis of clickable, semi-synthetic lipids, we introduced a chemically tractable, biologically active variant of the virulence lipid phthiocerol dimycocerosate (PDIM) into the mycomembrane. We find that following infection of zebrafish larvae, PDIM spreads away from bacterial surfaces into the membranes of both macrophage and epithelial cells that it contacts. This spreading facilitates PDIM′s role in preventing bacterium-detrimental immune activation at the site of infection.

Angewandte Chemie, 2015

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance... more The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance,b ut has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichiometric phosphine oxide and hydrazine by-products that complicate purification. Ac atalytic Mitsunobu reaction using innocuous reagents to recycle these by-products would overcome both of these shortcomings.Herein we report aprotocol that is catalytic in phosphine (1-phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchis azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction. Scheme 1. Proposed catalytic Mitsunobu reaction.

Synthesis, 2018

A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The prepar... more A simple, one-pot, and high-yielding synthesis of 1,3-diphenyldisiloxane is presented. The preparation of similar symmetrical disiloxane materials is also accomplished with this same protocol. This mechano-chemical procedure is efficient and highly scalable, furnishing a convenient route to hydrido-disiloxanes from widely accessible commercially available silanes.

Chemistry, a European Journal, 2017

Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward... more Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward method to prepare these valuable reagents. However, existing methods to reduce phosphine oxides suffer from inadequate chemoselectivity due to the strength of the P=O bond and/or poor atom economy. Herein, we report the discovery of the most powerful chemoselective reductant for this transformation to date, 1,3-diphenyl-disiloxane (DPDS). Additive-free DPDS selectively reduces both secondary and tertiary phosphine oxides with retention of configuration even in the presence of aldehyde, nitro, ester, a,b-unsaturated carbonyls, azocarboxylates, and cyano functional groups. Arrhenius analysis indicates that the activation barrier for reduction by DPDS is significantly lower than any previously calculated silane reduction system. Inclusion of a catalytic Brønsted acid further reduced the activation barrier and led to the first silane-mediated reduction of acyclic hosphine oxides at room temperature.

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates, 2016

The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel trea... more The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. Tuberculosis (TB) causes over 1.7 million deaths per year and an estimated two billion people latently infected with Mycobacterium tuberculosis provides a large reservoir for ongoing reactivation and transmission of disease 1,2. Treatment options for TB are longer and more complex than treatments for other bacterial infections. These complex therapies have led to patient non-compliance and disrupted treatment, resulting in an increased incidence of multidrug resistant and extensively drug resistant M. tuberculosis infections 1,3. The search for new therapeutic options for treatment of drug susceptible as well as drug resistant strains has fueled an effort to repurpose existing drugs for TB therapy 4,5. Sulfonamides are broad spectrum antimicrobials commonly used to treat many bacterial infections 6,7. These compounds are structurally similar to p-aminobenzoic acid (PABA), an essential precursor for synthesis of tetrahydrofolate. This structural similarity enables competitive inhibition of dihydropteroate synthase (DHPS) by sulfonamides thereby leading to disruption of tetrahydrofolate biosynthesis (Fig. 1a) 9. In addition, it has been shown that sulfonamides can serve as alternative substrates for DHPS leading to the depletion of dihydropterin pools with the synthesis of dead end products that might further impair tetrahydrofolate bio-synthesis 9,10. Sulfonamides were used in early experimental TB therapy, but were replaced by the more potent anti-tubercular agents streptomycin and p-aminosalicylic acid (PAS) 11-13. Dapsone, another PABA analog and DHPS inhibitor, is a cornerstone in treatment of infections with the related species Mycobacterium leprae. Yet, due to moderate potency and the extent of adverse drug reactions, this drug is not used for M. tuberculosis infections. Despite the limited utility of sulfonamides and dapsone against M. tuberculosis infection, enzy-matic studies have confirmed that these compounds are potent competitive inhibitors for purified recombinant

Angewandte Chemie International Edition, 2015

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance... more The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance,b ut has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichio-metric phosphine oxide and hydrazine by-products that complicate purification. Ac atalytic Mitsunobu reaction using innocuous reagents to recycle these by-products would overcome both of these shortcomings.Herein we report aprotocol that is catalytic in phosphine (1-phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchis azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.

Synthesis, 2013

A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyri... more A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyridine is presented. 5,5′-Bis(trifluoromethyl)-2,2′-bipyridine
is also synthesized by the same protocol. The syntheses efficiently couple the parent 2-chloropyridines by a nickel-catalyzed dimerization with manganese powder as the terminal reductant.

Synlett, 2014

The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two different el... more The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two different electrophiles, 2-chloropyridines with alkyl bromides, is described. Compared to our previously published conditions for aryl halides, this method uses the different, more rigid bathophenanthroline ligand and is conducted at high concentration in DMF solvent. The method displays promising functional group compatibility and the conditions are orthogonal to the Stille coupling.